Current smoking cessation treatments are ineffective for the majority of smokers. Thus there is an urgent need to develop more effective treatment strategies. This project will comprise two large-scale randomized controlled clinical trials designed to evaluate the efficacy of an enhanced adaptive treatment strategy for smoking cessation. The essence of our unique approach to adaptive treatment is to begin treatment with state-of-the-art nicotine replacement therapy (NRT), which is initiated 2 weeks before a target quit-smoking date. We will subsequently adapt the treatment approach based on smokers' initial response to NRT and other baseline variables assessed prior to the target quit date. Our overarching hypothesis is that we will enhance cessation outcomes by adapting phannacologic treatments based on individual subject characteristics and ad lib smoking during the time when smokers are receiving pre-cessation NRT. Study 1, to be conducted in years 1-3, will evaluate a specific two-phase adaptive treatment algorithm. We will initiate pre-cessation nicotine patch treatment 2 weeks before a target quit-smoking date. If, after one week's exposure to NRT, participants do not show a favorable therapeutic response (assessed by the early outcome marker of reduced ad lib smoking before the quit date), they will be randomized to receive rescue treatments with bupropion SR (Zyban), varenicline (Chantix), or will remain on NRT (control). Study 2, to be conducted in years 4-5, will evaluate an additional candidate medication, using the same adaptive treatment strategy as in Study 1. The selection of the candidate treatment will be based on available preclinical and clinical evidence from the other center projects as well as findings from other laboratories, using criteria described in the Research Plan. Candidate medications will include the neurosteroids DHEA and pregnenolone, other GABAergic, glutamatergic, or monoaminergic agents as well as nicotinic subtype selective ligands. Clinical trial decisions and results will be enhanced by information on individual subject characteristics, including quit success genotypes, dependence level, gender, as well as psychiatric and substance use comorbidities. Combined information from these baseline characteristics and smoking during pre-cessation NRT are likely to provide powerful predictors of which medication and treatment regimens are most likely to succeed for different smokers. The knowledge gained from these studies will provide an important new therapeutic approach to guide health care providers in delivering the most effective cessation treatments that are best adapted to the needs of each smoker.